Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1β Production and Activation through CD47.

Thrombospondin-1regulates inflammation by engaging several cell surface receptorsand by modulating activities of other secreted factors. We have uncovered a novel role of thrombospondin-1in modulating production and activation of the proinflammatory cytokine IL-1β by human and murine macrophages. Physiological concentrations of thrombospondin-1limit the induction by lipopolysaccharideof IL-1β mRNA and total protein production by human macrophages. This inhibition can be explained by the ability of thrombospondin-1to disrupt the interaction between CD47and CD14, thereby limiting activation of NFκB/AP-1 by lipopolysaccharide. Only the CD47- binding domainof thrombospondin-1exhibits this activity. In contrast, CD47, CD36, and integrin- binding domainsof thrombospondin-1independently enhance the inflammasome-dependent maturation of IL-1β in human THP-1 monocyte-derived macrophages. Correspondingly, mouse bone marrow-derived macrophagesthat lack either thrombospondin-1or CD47exhibit diminished induction of mature IL-1β in response to lipopolysaccharide. Lack of CD47also limits lipopolysaccharideinduction of IL-1β, NLRP3, and caspase-1mRNAs. These data demonstrate that thrombospondin-1exerts CD47-dependent and -independent pro-and anti-inflammatory effects on the IL-1β pathway. Therefore, thrombospondin-1and its receptor CD47may be useful targets for limiting the pro-inflammatory effects of lipopolysaccharideand for treating endotoxemia.